This is a proposal for a Pathway to Independence award for Youko Ikeda, Ph.D., who has been investigating the mechanisms that cause alterations in the intrinsic/spontaneous activity of the bladder following spinal cord injury as part of her postdoctoral training at the University of Pittsburgh. The current goal of the candidate is to establish an independent line of research and develop skills such as grantsmanship and establishing collaborations, necessary for the long-term goal of starting an independent research laboratory. The research proposal presented here will be based on the role of urinary bladder interstitial cells (IC) in detrusor overactivity. It is well established that urothelial cells that line the bladder release chemical factors in response to mechanical distension. However, the mechanism by which these signals are transduced from the urothelium to influence bladder activity and their specific targets is not entirely clear. In this application, we will characterize the properties of bladder IC and their potential as a communication network to transduce signals from the urothelium to the rest of the bladder wall. From published and preliminary data, it has been demonstrated that IC in the bladder form an intricate network that extends throughout the bladder wall, with a dense plexus in the suburothelial region. In addition, they appear to be coupled via gap junctions and show potential to respond to urothelially-released chemical mediators. Of particular interest are the cells in the suburothelium, which have been shown to be functionally different to those found in the detrusor layer and may respond more readily to urothelial factors. In this proposal the overall aim is to characterize the physiological properties of bladder IC in normal and pathological bladders, specifically those related to their ability to act as signal transducers within the bladder wall. There are three specific aims outlined: 1) Characterize the spontaneous activity, evoked responses and release of chemical factors in cultured suburothelial IC from normal and spinal cord transected (SCT) rat bladders 2) Examine the ability of cultured suburothelial IC to act as a communication network and their interactions with urothelial and detrusor smooth muscle cells 3) Evaluate the effect of modulating IC communication on the function of normal and pathological bladders in vitro and in vivo These studies will give insight into a unique communication mechanism within the bladder and may potentially lead to the elucidation of alternative therapeutic targets for overactive bladder symptoms. PUBLIC HEALTH RELEVANCE: This proposal will investigate mechanisms of communication between the different cell layers of the bladder. Specifically through the extensive network of interstitial cells that spread throughout the bladder wall, and how these may affect bladder function. It is hypothesized that changes in the interaction of cells within the bladder may contribute to Overactive Bladder (OAB) symptoms. OAB symptoms affect a significant number of the US population and profoundly reduce the quality of life of these individuals. The underlying causes for some of those with OAB are not always clear. We believe further understanding of the interactions within the bladder will elucidate mechanisms that contribute to OAB symptoms and potentially, new therapeutic targets.